Process for preparing indane-like compounds

ABSTRACT

The present invention provides intermediate for the preparation of indane-like compounds which are useful for the modulation of a muscarinic receptor.

This application is a continuation of Provisional Application Ser. No.60/035,428, filed Jan. 22, 1997, and is a 371 of PCT/US98/01145 filedJan. 21, 1998.

The present invention relates an improved process and intermediates forpreparing novel indane-like compounds.

The novel indane-like compounds prepared using the presently claimedprocess and intermediates have useful muscarinic receptor activity.Thus, the compounds prepared using the process and intermediates of thisinvention can be useful for the treatment of conditions associated withthe modulation of a muscarinic receptor. For example, such conditionsinclude, but are not limited to psychosis, Alzheimer's Disease,glaucoma, pain, bladder dysfunction, irritable bowel syndrome, andParkinsonism.

The previous processes for preparing such indane-like compounds aretedious and do not provide an efficient mechanism for rapid synthesis.The presently claimed invention addresses this need for a more efficientprocess for preparing novel indane-like compounds.

The present invention provides a process for preparing a compound of theFormula I:

R¹ is selected from the group consisting of hydrogen, —OR⁴, —SR⁵, C₁-C₃alkyl, C₂-C₃ alkenyl, halo, —CN, S (O)_(m2), —COR^(4b′), and —OC(O)—R¹⁵;

m2 is from 0 to 2;

R² is selected from the group consisting of C₁-C₁₀ alkyl, substitutedC₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, substituted C₂-C₁₀ alkenyl, C₃-C₈cycloalkyl, substituted C₃-C₈ cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic;

R⁴ is hydrogen, C₁-C₃ alkyl;

R⁵ is hydrogen, C₁-C₃ alkyl;

R¹⁰ is selected from the group consisting of hydrogen, carbonyl, halo,and C₁-C₃ alkyl;

R¹¹ is selected from the group consisting of hydrogen and C₁-C₃ alkyl;

R¹² is independently selected from the group consisting of hydrogen,C₁-C₁₀ alkyl, and aryl;

R¹³ is independently selected from the group consisting of hydrogen,C₁-C₁₀ alkyl, and aryl; or

R¹² and R¹³ together with the nitrogen to which they are attached form agroup of the formula II:

or

II′ wherein the III group is a group of Formula II which is unsaturated;or

R¹¹ and R¹² together with the nitrogen and carbon to which they arebound can join to form a three to six membered ring;

R¹⁴ is selected from the group consisting of H, halo, C₁-C₃ alkyl,S(O)_(m3) and —OR¹⁶;

R¹⁵ is C₁-C₃ alkyl or aryl;

R¹⁶ is C₁-C₃ alkyl;

R¹⁷ is independently selected from the group consisting of hydrogen,—OR^(4′), —SR^(5′), C₁-C₃ alkyl, C₂-C₃ alkenyl, halo, —CN, S(O)_(m2′),—COR^(4b), and —OC(O)—R^(15′);

R^(4b) and R^(4b′) are each independently selected from hydrogen andC₁-C₃ alkyl;

R^(15′) is C₁-C₃ alkyl or aryl;

m2′ is 0 to 2;

R^(4′) is hydrogen, C₁-C₃ alkyl;

R^(5′) is hydrogen, C₁-C₃ alkyl;

m2 is 0 to 2;

X is selected from the group consisting of C, O, S, N, carbonyl, and abond;

n′ is 0 to 2;

m′ is 0 to 2;

m3 is 0 to 2;

n is 0 to 3; or

a pharmaceutically acceptable salt or solvate thereof; comprisingcoupling a compound of the formula

with a compound of the formula

R²¹ and R²² are selected from H and O;

R²⁰ is selected from amine protecting groups;

R^(1′) is selected from the group consisting of —OR⁴, —SR⁵, C₁-C₃ alkyl,C₂-C₃ alkenyl, halo, —CN, S(O)_(m2), —COR^(4b′), and —OC(O)—R¹⁵;

m2 is 0 to 2;

R⁴ and R^(4b′) are each independently selected from hydrogen and C₁-C₃alkyl;

R⁵ is selected from hydrogen and C₁-C₃ alkyl; R¹⁵ is C₁-C₃ alkyl oraryl.

A further embodiment of this invention is the a process comprisingcatalytic hydrogenation of a compound of the formula

wherein both R²¹ and R²² are each O; to form a compound wherein both R²¹and R²² are each H;

R²¹ and R²² are selected from H and O;

R²⁰ is selected from amine protecting groups;

R^(1′) is selected from the group consisting of —OR⁴, —SR⁵, C₁-C₃ alkyl,C₂-C₃ alkenyl, halo, —CN, S(O)_(m2), —COR^(4b′), and —OC(O)—R¹⁵;

m2 is 0 to 2;

R⁴ and R^(4b′) are each independently selected from hydrogen and C₁-C₃alkyl;

R⁵ is selected from hydrogen and C₁-C₃ alkyl; R¹⁵ is C₁-C₃ alkyl oraryl.

Additionally, this invention provides a process for preparing a compoundof the Formula I′

R¹ is selected from the group consisting of hydrogen, —OR⁴, —SR⁵, C₁-C₃alkyl, C₂-C₃ alkenyl, halo, —CN, S(O)_(m2), —COR^(4b′), and —OC(O)—R¹⁵;

m2 is from 0 to 2;

R² is selected from the group consisting of C₁-C₁₀ alkyl, substitutedC₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, substituted C₂-C₁₀ alkenyl, C₃-C₈cycloalkyl, substituted C₃-C₈ cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic;

R⁴ is hydrogen, C₁-C₃ alkyl;

R⁵ is hydrogen, C₁-C₃ alkyl;

R¹⁰ is selected from the group consisting of hydrogen, carbonyl, halo,and C₁-C₃ alkyl;

R¹¹ is selected from the group consisting of hydrogen and C₁-C₃ alkyl;

R¹² is independently selected from the group consisting of hydrogen,C₁-C₁₀ alkyl;

R¹³ is independently selected from the group consisting of hydrogen,C₁-C₁₀ alkyl; and

R¹² and R¹³ together with the nitrogen to which they are attached form agroup of the formula II:

R¹⁴ is selected from the group consisting of H, halo, C₁-C₃ alkyl,S(O)_(m3) and —OR¹⁶;

R¹⁵ is C₁-C₃ alkyl or aryl;

R¹⁶ is C₁-C₃ alkyl;

R¹⁷ is independently selected from the group consisting of hydrogen,—OR^(4′), —SR^(5′), C₁-C₃ alkyl, C₂-C₃ alkenyl, halo, —CN, S(O)_(m2′),COR^(4b), and —OC(O)—R^(15′);

R^(4b) and R^(4b′) are each independently selected from hydrogen andC₁-C₃ alkyl;

R^(15′) is C₁-C₃ alkyl or aryl;

m2′ is 0 to 2;

R^(4′) is hydrogen, C₁-C₃ alkyl;

R^(5′) is hydrogen, C₁-C₃ alkyl;

m2 is 0 to 2;

X is selected from the group consisting of C, O, S, N, carbonyl, and abond;

n′ is 0 to 2;

m′ is 0 to 2;

m3 is 0 to 2;

n is 0 to 3;

comprising contacting a neat amine with a catalytic acid to provide thedesired compounds of Formula I′.

The present invention provides compounds of the Formula III′

.R¹ is selected from the group consisting of hydrogen, —OR⁴, —SR⁵, C₁-C₃alkyl, C₂-C₃ alkenyl, halo, —CN, S(O)_(m2), —COR^(4b′), and —OC(O)—R¹⁵;

m2 is from 0 to 2;

R⁴ is hydrogen, C₁-C₃ alkyl;

R⁵ is hydrogen, C₁-C₃ alkyl;

R¹⁰ is selected from the group consisting of hydrogen, carbonyl, halo,and C₁-C₃ alkyl;

R¹¹ is selected from the group consisting of hydrogen and C₁-C₃ alkyl;

R¹² is independently selected from the group consisting of hydrogen,C₁-C₁₀ alkyl, and aryl;

R¹³ is independently selected from the group consisting of hydrogen,C₁-C₁₀ alkyl, and aryl; or

R¹² and R¹³ together with the nitrogen to which they are attached form agroup of the formula II:

or

II′ wherein the II′ group is a group of Formula II which is unsaturated;or

R¹¹ and R¹² together with the nitrogen and carbon to which they arebound can join to form a three to six membered ring;

R¹⁴ is selected from the group consisting of H, halo, C₁-C₃ alkyl,S(O)_(m3) and —OR¹⁶;

R¹⁵ is C₁-C₃ alkyl or aryl;

R¹⁶ is C₁-C₃ alkyl;

R¹⁷ is independently selected from the group consisting of hydrogen,—OR^(4′), —SR^(5′), C₁-C₃ alkyl, C₂-C₃ alkenyl, halo, —CN, S(O)_(m2′),—COR^(4b), and —OC(O)—R^(15′);

R^(4b) and R^(4b′) are each independently selected from hydrogen andC₁-C₃ alkyl;

R^(15′) is C₁-C₃ alkyl or aryl;

m2′ is 0 to 2;

R^(4′) is hydrogen, C₁-C₃ alkyl;

R^(5′) is hydrogen, C₁-C₃ alkyl;

m2 is 0 to 2;

X is selected from the group consisting of C, O, S, N, carbonyl, and abond;

n′ is 0 to 2;

m′ is 0 to 2;

m3 is 0 to 2;

n is 0 to 3;

R²⁰ is selected from amine protecting groups; or

a pharmaceutically acceptable salt or solvate thereof.

Additionally, this invention provides a formulation comprising acompound of Formula III′ and one or more pharmaceutically acceptableexcipients or carriers there for.

The substituent of Formula II can be from a 3-member to 8 member ring.The substituent of Formula II′ is unsaturated. Formula II′ is optionallyaromatic, but is in no way required to be aromatic. It may be preferredthat Formula II′ contains from one to two double bonds.

The term “interacting with a muscarinic receptor” refers to a compoundacting as a muscarinic receptor agonist, antagonist, or partial agonist.Most preferably, the compounds of this invention will act as an agonistof a muscarinic receptor. It is especially preferred that a compound ofthis invention will selectively interact with a m4 muscarinic receptorsubtype. Further it is particularly preferred that a compound of thisinvention will act as a selective m4 muscarinic receptor agonist.

The terms “C₁-C_(m) alkyl” wherein m=2-10, as used herein, represent abranched or linear alkyl group having from one to the specified numberof carbon atoms. For example, typical C₁-C₆ alkyl groups include methyl,ethyl, n-propyl, iso-propyl, butyl, a so-butyl, sec-butyl, tert-butyl,pentyl, hexyl and the like.

The term “substituted C₁-C_(m) alkyl” refers to an alkyl group which issubstituted with from one to five selected from the group consisting ofC₂-C₆ alkenyl, halo, —CF₃, —OR^(4a), —SR^(5a), —CO₂R^(6a), halo, C₃-C₈cycloalkyl, substituted C₄-C₈ cycloalkyl, and —CN; wherein 4a, 5a, and6a are each independently selected from the group consisting ofhydrogen, C₁-C₃ alkyl, aryl and substituted aryl.

The term “carbonyl” has the meaning commonly attributed to the term bythe skilled artisan. For example, ═O.

The terms “C₂-C_(n) alkenyl” wherein n=3-10, as used herein, representsan olefinically unsaturated branched or linear group having from 2 to 10carbon atoms and at least one double bond. The groups can be branched orstraight chain. Examples of such groups include 1-propenyl, 2-propenyl(—CH₂—CH═CH₂), 1-butenyl (—CH═CHCH₂CH₃), 1,3-butadienyl (—CH═CHCH═CH₂),hexenyl, pentenyl, and the like.

The terms “halide”, “halogen”, and “halo” include fluorine, chlorine,bromine, and iodine. The preferred halogen is chlorine.

The term “C₃-C_(n) cycloalkyl” wherein n=4-8, represents cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and thelike.

The term “hererocyclic” refers to a heterocyclic ring having from fourto eight members and from one to three non-carbon atoms selected fromthe group consisting of N, O, and S; or a combination thereof, and whichheteroaryl group is optionally fused with a phenyl group.

The term “substituted heterocyclic” refers to a heterocyclic group whichmay be substituted with from one to three substituents selected from thegroup consisting of halogen(s), —CF₃, NO₂, —CN, C₁₋₁₅-alkyl,C₂₋₅-alkenyl, C₂₋₅-alkynyl, COR^(6a), —OR^(4a), —SR^(5a), C₃-C₈cycloalkyl, C₅-C₈ cycloalkenyl, substituted C₃-C₈ cycloalkyl,substituted C₅-C₈ cycloalkenyl, and aryl; wherein 4a, 5a, and 6a areeach independently selected from hydrogen, —CF₃, C₁-C₃ alkyl, aryl, and—C₁-C₃ alkyl-aryl.

The term “substituted(C₅-C_(n)) cycloalkyl” refers to a cycloalkyl groupas described supra wherein the cycloalkyl group may be substituted withfrom one to four substituents independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, NO₂, halo,halo(C₁-C₆)alkyl, halo(C₂-C₆)alkenyl, C₂-C₆ alkenyl, C₃-C₈cycloalkyl-(C₁-C₃)alkyl, C₅-C₈ cycloalkenyl, C₅-C₈cycloalkenyl-(C₁-C₃)alkyl, COR_(5a), C₁-C₁₀ alkanoyl, C₇-C₁₆ arylalkyl,CO₂R_(5a), (C₁-C₆ alkyl)_(m)amino, —SR_(5a), and OR_(5a); wherein 5a isselected from hydrogen and C₁-C₃ alkyl; m is from one to two.

The term “C₃-C₈ cycloalkyl-(C₁-C₃)alkyl” represents a linear alkyl groupsubstituted at a terminal carbon with a C₃-C₈ cycloalkyl group. Typicalcycloalkylalkyl groups include cyclohexylethyl, cyclohexylmethyl,3-cyclopentylpropyl, and the like.

The term “C₅-C₈ cycioaikenyl” represents an olefinically unsaturatedring having five to eight carbon atoms, eg., cyclohexadienyl,cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl,cyclohexadienyl, cycloheptadienyl, cyclooctatrienyl and the like. Thecycloalkenyl group may be substituted with from one to four substituentsselected from the group consisting of hydrogen, C₁-C₆ alkyl, NO₂, halo,halo(C₁-C₆)alkyl, halo(C₂-C₆)alkenyl, C₂-C₆ alkenyl, (C₁-C₆alkyl)_(m)amino, COR₅, C₁-C₁₀ alkanoyl, OR₅, CO₂R₅, —SR₅, and C₇-C₁₆arylalkyl.

The term “C₅-C₈ cycloalkenyl-(C₁-C₃)alkyl-” represents a linear C₁-C₃alkyl group substituted at a terminal carbon with a C₅-C₈ alkenyl group.

As used herein the term “carboxy” refers to a substituent having thecommon meaning understood by the skilled artisan, wherein the point ofattachment may be through the carbon or oxygen atom of the group.

As used herein the term “aryl” means an organic radical derived from anaromatic hydrocarbon by the removal of one atom. For example, the termincludes, but is in no way limited to biphenyl, phenyl or naphthyl. Theterm “aryl” refers to hydrocarbon aryl groups. Most preferably, arylrefers to C₆-C₁₀ aryl, wherein the aryl ring system, including any alkylsubstitutions, comprises from 6 to 10 carbon atoms; e.g., phenyl,3,3-dimethylphenyl, naphthyl, and the like. The aryl radical may besubstituted by one or two C₁-C₆ straight or branched alkyl. The arylgroup may be fused with a heteroaryl or heterocyclic.

“Substituted aryl” refers to an aryl group which may be substituted withfrom one to three substituents selected from the group consisting ofhalogen(s), —CF₃, NO₂, —CN, C₁₋₁₅-alkyl, C₂₋₅-alkenyl, C₂₋₅-alkynyl,—COR^(6a), —OR^(4a), —SR^(5a), C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl,substituted C₃-C₈ cycloalkyl, substituted C₅-C₈ cycloalkenyl, and aryl;wherein 4a, 5a, and 6a are each independently selected from hydrogen,—CF₃, C₁-C₃ alkyl, aryl, and —C₁-C₃ alkyl-aryl. The substituents may belocated at any available position on the ring, provided that there isnot more than one substituent selected from the group consisting ofaryl, C₃-C₈ cycloalkyl, substituted C₃-C₈ cycloalkyl, C₅-C₈cycloalkenyl, and substituted C₅-C₈ cycloalkenyl.

As used herein, the phrase “heteroaryl” means an aryl group containingfrom one to three N, O or S atom(s) or a combination thereof, and whichheteroaryl group is optionally fused with a phenyl group. The phrase“heteroaryl” includes, but is not limited to, 5-membered heteroarylshaving one hetero atom (e.g. thiophenes, pyrroles, furans); 5-memberedheteraryls having two heteroatoms in 1,2 or 1,3 positions (e.g.oxazoles, pyrazoles, imidazoles, thiazoles, purines); 5-memberedheteraryls having three heteroatoms (e.g. triazoles, thiadiazoles);5-membered heteraryls having 3-heteroatoms; 6-membered heteroaryls withone heteroatom (e.g. pyridine, quinoline, isoquinoline, phenanthrine,5,6-cycloheptenopyridine); 6-membered heteraryls with two heteroatoms(e.g. pyridazines, cinnolines, phthalazines, pyrazines, pyrimidines,quinazolines); 6-membered heteroaryls with three heteroatoms (e.g.1,3,5-triazine); and 6-member heteroaryls with four heteroatoms.Particularly preferred are benzothiophenes, pyridines, and furans. Mostpreferredly, the heteroaryl group is a four to eight membered ring.

The term “substituted heteroaryl” refers to a heteroaryl group which issubstituted at carbon or nitrogen atom(s) with C₁₋₆-alkyl, —CF₃, phenyl,benzyl, substituted aryl or thienyl, or a carbon atom in the heteroarylgroup together with an oxygen atom form a carbonyl group. Suchsubstituted heteroaryl may optionally be fused with a phenyl group.

The term “amine protecting group” is used herein as it is frequentlyused in synthetic organic chemistry, to refer to a group which willprevent an amine group from participating in a reaction carried out onsome other functional group of the molecule, but which can be removedfrom the amine when it is desired to do so. Such groups are discussed byT. W. Greene in chapter 7 of Protective Groups in Organic Synthesis,John Wiley and Sons, New York, 1981, J. F. W. McOmie, which areincorporated herein by reference in their entirety. Examples of amineprotecting groups include benzyl and substituted benzyl such as3,4-dimethoxybenzyl, o-nitrobenzyl, and triphenylmethyl; those of theformula —COOR where R includes such groups as methyl, ethyl, propyl,isopropyl, 2,2,2-trichloroethyl, 1-methyl-1-phenylethyl, isobutyl,t-utyl, t-amyl, vinyl, allyl, phenyl, benzyl, p-nitrobenzyl,o-nitrobenzyl, and 2,4-dichlorobenzyl; acyl groups and substituted acylsuch as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl,trifluoroacetyl, benzoyl, and p-methoxybenzoyl; and other groups such asmethanesulfonyl, p-toluenesulfonyl, p-bromobenzenesulfonyl,p-nitrophenylethyl, and p-toluenesulfonylaminocarbonyl. A preferredamino-blocking group is t-butoxycarbonyl.

The term “C₇-C₁₆ arylalkyl” represents an aryl-(C₁-C₁₀)alkyl substituentwherein the alkyl group is linear, such as but not limited to, benzyl,phenethyl, 3-phenylpropyl, or phenyl-t-butyl; or branched. The arylalkyl moitety is attached to the parent nucleus via the alkyl group.

The term “organic solvent” includes solvents containing carbon, such ashalogenated hydrocarbons, ether, toluene, xylene, benzene, andtetrahydrofuran.

The term “agitate” includes such techniques as stirring, centrifugation,mixing, and other similar methods.

The abbreviations used herein have their accepted meaning, unless statedotherwise. Such accepted meaning shall be the meaning attributed to suchterm by the skilled artisan or the American Chemical Society.

The terms “MeO” and “EtO” refer to methoxy and ethoxy substituents whichare bound to the parent molecule through the oxygen.

The previous method for generating the indane scaffold used in thisinvention for compound forming purposes comprised the followingsequential steps:

1. Nitration of indanone starting yields nitroindanone which is thenseparated from minor component byproducts.

2. The product of step 1 is reduced to give the corresponding alcohol.

3. The product of step 2 is then subjected to an acid catalyzeddehydration to give the corresponding indene.

4. The double bond of the product of step 3 is oxidized to give theepoxide.

5. The product epoxide 4 is then reacted with ammonium hydroxide to givethe amino alcohol.

6. The amino alcohol of step 5 is protected with a conventionalprotecting group.

The preceding method of indane scaffold preparation is furtherillustrated by the following reaction scheme:

The formation of indane compounds in these libraries is accomplishedusing polymer bound reaction schemes generally described as follows:

A) A polymer bearing a carboxylic acid functionality is coupled with theprotected indane of the following formula:

B) The reactants of step (A) are coupled;

C) The product of step (B) is deprotected resulting in an aminefunctional indane bound to a resin support;

D) The product of step (C) is acylated to attach a first diverse group,E₁ ⁺;

E) The product of step (D) is reduced to give the corresponding aniline;

F) The product of step (E) is again acylated to attach a second diversegroup, E₂ ⁺;

G) Cleavage with a base of the product of step (E) from the polymerresults in the formation of the product characterized by the formula:

Indane Library and Compound Forming Process Description

The process steps, more fully described below in the PreparationSection, are illustrated by the following reaction Scheme IA:

Multiple simultaneous synthesis may be performed by a variety ofapparatus, such as that shown for multiple simultaneous synthesis U.S.Pat. No. 5,324,483; the disclosure of which is incorporated herein byreference.

The compounds of this invention can be prepared using the followinggeneral techniques. The skilled artisan will appreciate that there arealternative methods to obtain the desired compounds claimed herein.

As illustrated by Scheme I, 1 which is commercially available or may beprepared by the skilled artisan using known methods, is dissolved in amixture of pyridine, 4-dimethylaminopyridine and an inert organicsolvent, wherein preferred inert organic solvents include but are notlimited to solvents such as THF or CH₂Cl₂, as acetyl chlorideis added.The mixture may be treated with cold water and the organic layerseparated. The organic solution is washed, the organic layer dried, andthe solvent evaporated to give 2. A solution of 2 in THF or antherappropriate solvent is treated with a stream of dry HCl. The solution istreated with most preferredly cold saturated sodium bicarbonate, theorganic phase was washed, dried and the solvent evaporated to give 3. Asolution of 3 in a mixture of pyridine, 4-dimethylaminopyridine, andCH₂Cl₂ is treated with a solution of an arylsulfonyl chloride and thereaction stirred. The reaction is most preferredly poured intoice-water, the organic layer separated and consecutively washed.Preferred washes are with 1 N HCl and brine. The organics are dried andthe solvent evaporated to five 14. A solution of 14 is treated wtihSnCl₂-2 H₂O. The reaction mixture is preferredly poured into ice-water,the reaction made basic, and the mixture extracted. The organic extractsare washed, the solution dried, and the solvent evaporated 15.Alternatively, a solution of 14 in EtOAc or THF is treated with H₂(about 60 psi) in the presence of a catalyst. Preferred catalysts arechosen from but not limited to the group consisting of PtO₂, Rainey-Ni,and Pd—C. The catalyst is removed and the solvent evaporated to give 15.A solution of 15 is treated with a solution of a chloroalkylenedialkylammonium chloride. It is noted here that the artisan shouldrecognize that other reagents analagous to chloroalkylidenedialkylammonium chloride can also provide the desired compounds. Thereaction was preferredly poured into ice-water, the organic layerseparated and consecutively washed. Preferred washes are with saturatedsodium bicarbonate and brine. The organics are dried and the solventevaporated to give 18. A solution of 18 in base is stirred. The reactionmixture is preferredly poured into ice-water and extracted. The organicextracts are washed, dried, and the solvent evaporated to give thedesired compound of this invention.

As illustrated by Scheme II, compounds of this invention can be preparedby a solution of a benzamide being treated with NaH and preferredly, thereaction mixture is stirred until gas evolution ceased.1,2-epoxy-6-nitroindane is added. Preferredly the1,2-epoxy-6-nitroindane is added at about 60 C and stirred. The reactionis preferredly poured into ice-water and extracted. The organic extractsare washed, dried, and the solvent evaporated. The residue ischromatographed to obtain 17. A solution of 17 in a mixture of pyridine, 4-dimethylaminopyridine and an inert organic solvent, for example butnot limited to solvents such as THF or CH₂Cl₂, as acetyl chloride isadded. The reaction is preferredly treated with cold water and theorganic layer separated. The organic solution is washed, dried, and thesolvent evaporated to give 14. Processing of 14 as in Scheme I providesthe desired compounds of this invention.

As illustrated by Scheme III, certain compounds of this invention can beprepared by a mixture of 6-nitroindan-1-one and a catalyst, which ispreferredly, but not limited to one chosen from PtO₂, Rainey-Ni, andPd—C in EtOH, is treated with hydrogen. The catalyst is removed and thesolvent evaporated to give 8. A solution of 8 in a mixture of pyridine,4-dimethylaminopyridine, and CH₂Cl₂ is treated with a solution of achloroalkylidene dialkylammonium chloride and the reaction mixture ispreferredly stirred. It is noted here that the artisan should recognizethat other reagents analagous to chloroalkylidene dialkylammoniumchloride can also provide the desired compounds. The reaction ispreferredly poured into ice-water, the organic layer separated andconsecutively washed. Preferred washes are with saturated sodiumbicarbonate and brine. The organics are dried and the solvent evaporatedto give 12. A solution of 12 in a mixture of lower alcohol and NH₃ istreated with hydrogen in the presence of a catalyst which is mostpreferredly, but not limited to, either Pd—C-sulfided or Pt—C sulfided.The catalyst is removed and the solvent evaporated to give 13. Asolution of 13 in a mixture of pyridine, 4-dimethylaminopyridine, andCH₂Cl₂ is treated with a solution of an arylsulfonyl chloride. Thereaction is preferredly poured into ice-water, the organic layerseparated and consecutively washed. Preferred washes are with saturatedsodium bicarbonate and brine. The organics are dried and the solventevaporated to give the desired compound of this invention.

Protection of the 3-amino group of compound 5, preferably as a carbamatesuch as t-butyl carbamate, under standard conditions¹ provided compound1 (also referred to as 6 supra.). Other similar protecting groups can beutilized in place of t-butyl carbamate. Carbamates are particularlypreferred protecting groups for the synthesis described by Step 1.

¹ Greene and Wuts, Protecting Groups in Organic Chemistry,

Step 2.

Reduction of the nitro group may be accomplished using reagents such asSnCl₂, NaBH₄, or more preferably using metal-catalyzed hydrogenation.²Most preferably, Pd/C was used in EtOH at 50 psi and ambienttemperature.

² Rylander, Hydrogenation

Step 3.

The amidine functionality of compounds 57-76 may be prepared from theamine by a variety of methods using reagents such as Gold's reagent.Most preferably the dimethyl amidine was prepared usingN,N-dimethylformamide dimethyl acetal under standard conditions.³

³ Patel amidine series and Meyers paper and ref. 4.

Step 4.

The amidine may be exchanged in the presence of higher boiling aminessuch as pyrollidine, piperidine, morpholine, or benzyl amine to providecompounds 6-56 and 77-105.⁴

⁴ Transamidination reaction references.

Step 5.

The t-butyl carbamate protecting group was removed under standardconditions (ref 1) using cold trifluoroacetic acid.

Step 6.

The trifluoroacetate salt of the amine was reacted with a variety ofacid chlorides in the presence of a base such as triethylamine at −10°C. to ambient temperature in a solvent such as methylene chloride toprovide compounds VII.

Step 7.

The alcohol group of compounds 5-105 may be acylated or alkylated withreagents such as acetic anhydride in the presence of a base such astriethylamine.

The compounds of this invention can form acid addition salts with a widevariety of inorganic and organic acids. Typical acids which can be usedinclude sulfuric, hydrochloric, hydrobromic, phosphoric, hypophosphoric,hydroiodic, sulfamic, citric, acetic, maleic, malic, succinic, tartaric,cinnamic, benzoic, ascorbic, mandelic, p-toluenesulfonic,benzenesulfonic, methanesulfonic, trifluoroacetic, hippuric and thelike. The pharmaceutically acceptable acid addition salts of thecompounds of this invention are especially preferred.

The compounds of the present invention are useful for modulating orblocking the M-1 receptor and can be useful for modulating or blocking aserotonin receptor. Certain of the present compounds are preferred forthat use. Preferred compounds and embodiments of this invention arethose having the following characteristics. The following preferredcharacteristics may be independently combined to provide furtherpreferred embodiments of this invention:

A) R³ is aryl;

B) R¹ is hydrogen;

C) R¹ is —OH;

D) R³ is substituted phenyl having 3,4-dichloro substituents;

E) R² is substituted phenyl having 3,4-dichloro or meta trifluoromethylsubstituents;

F) n is one;

G) the indane ring is saturated;

H) R³ is bicycloaryl;

I) R³ is substituted phenyl having a meta NO₂ substituent;

J) R³ is C₁-C₄ alkyl;

K) R³ is substituted C₁-C₆ alkyl wherein the terminal carbon of thealkyl chain is substituted with CO₂R⁴ wherein R⁴ is hydrogen, methyl, orethyl;

L) R¹ is OH, n is 1 and the OH group is located at the 2 position of thering;

M) a compound of this invention is used for treating psychosis;

N) A compound of Formula I:

Further, the present invention contemplates both the cis and transstereoisomers of the compounds of Formula I. The trans configuration ispreferred.

The present invention contemplates racemic mixtures as well as thesubstantially pure enantiomers of the compounds of Formula I. The term“enantiomer” is used herein as commonly used in organic chemistry todenote a compound which rotates the plane of polarization. Thus, the “−enantiomer” rotates the plane of polarized light to the left, andcontemplates the levorotary compound of Formula I. The + and −enantiomers can be isolated using classical resolution techniques. Oneparticularly useful reference which describes such methods is Jacqueset. al. Enantiomers, Racemates, and Resolutions (John Wiley and Sons1981). Appropriate resolution methods include direct crystallization,entrainment, and crystallization by optically active solvents. Chrisey,L. A. Heterocycles, 267, 30 (1990). A preferred resolution method iscrystallization by an optically active acid or by chiral synthesis usingthe method of A. I. Meyers. Loewe, M. F. et al., Tetrahedron Letters,3291, 26 (1985), Meyers, A. I. et al., J. Am. Chem. Soc. 4778, 110(1988). Preferred optically active acids include camphorsulfonic andderivatives of tartaric acid.

The compounds of the present invention are known to form hydrates andsolvates with appropriate solvents. Preferred solvents for thepreparation of solvate forms include water, alcohols, tetrahydrofuran,DMF, and DMSO. Preferred alcohols are methanol and ethanol. Otherappropriate solvents may be selected based on the size of the solventmolecule. Small solvent molecules are preferred to facilitate thecorresponding solvate formation. The solvate or hydrate is typicallyformed in the course of recrystallization or in the course of saltformation. One useful reference concerning solvates is Sykes, Peter, AGuidebook to Mechanism in Organic Chemistry, 56+, 6th Ed (1986, JohnWiley & Sons, New York). As used herein, the term “solvate” includeshydrate forms, such as monohydrates and dihydrates.

The column chromatography procedures used standard flash chromotagraphytechniques. One well-known reference describing appropriate flashchromotagraphy techniques is Still, W. C. Kahn, and Mitra, J. Org. Chem.1978, 43, 2932. Fractions containing product were generally evaporatedunder reduced vacuum to provide the product.

Optical rotations were obtained using methanol, pyridine, or othersuitable solvent.

The hydrochloride salt of the particular compound was prepared byplacing the free base into diethyl ether.

While stirring this ether solution, a solution of HCl in diethyl etherwas added dropwise until the solution became acidic. Alternatively, theether solution was treated with dry HCl gas.

The maleate salt of the particular compound was prepared by placing thefree base in ethyl acetate and treating with maleic acid. Theprecipitate formed was filtered and dried to provide the correspondingmaleate salt of the free base.

I. Muscarinic Activity.

As used herein the term “malfunctioning of the muscarinic cholinergicsystem” shall have the meaning accepted by the skilled artisan. Forexample the term shall refer to, but is not in any way limited to,conditions such as glaucoma, psychosis, schizophrenia orschizophreniform conditions, depression, sleeping disorders, epilepsy,and gastrointestinal motility disorders. Other such conditions includeAlzheimer's Disease and incontinence.

The pharmacological properties of the compounds of the invention can beillustrated by determining their capability to inhibit the specificbinding of ³H-Oxotremorine-M (³H-Oxo). Birdsdall N. J. M., Hulme E. C.,and Burgen A. S. V. (1980). “The Character of Muscarinic Receptors inDifferent Regions of the Rat Brain”. Proc. Roy. Soc. London (Series B)207,1.

³H-Oxo labels muscarinic receptor in the CNS (with a preference foragonist domains of the receptors). Three different sites are labeled by³H-Oxo. These sites have affinity of 1.8, 20 and 3000 nM, respectively.Using the present experimental conditions only the high and mediumaffinity sites are determined.

The inhibitory effects of compounds on ³H-oxo binding reflects theaffinity for muscarinic acetylcholine receptors.

All preparations are performed at 0-4° C. unless otherwise indicated.Fresh cortex (0.1-1 g) from male Wistar rats (150-250 g) is homogenizedfor 5-10 s in 10 mL 20 nM Hepes pH: 7.4, with an Ultra-Turraxhomogenizer. The homogenizer is rinsed with 10 mL of buffer and thecombined suspension centrifuged for 15 min. at 40,000×g. The pellet iswashed three times with buffer. In each step the pellet is homogenizedas before in 2×10 mL of buffer and centrifuged for 10 min. at 40,000×g.

The final pellet is homogenized in 20 mM Hepes pH: 7.4 (100 mL per g oforiginal tissue) and used for binding assay. Aliquots of 0.5 mL is added25 μL of test solution and 25 μL of ³H-Oxotremorine (1.0 nM, finalconcentration) mixed and incubated for 30 min. at 25° C. Non-specificbinding is determined in triplicate using arecoline (1 μg/mL, finalconcentration) as the test substance. After incubation samples are added5 mL of ice-cold buffer and poured directly onto Whatman GF/C glassfiber filters under suction and immediately washed 2 times with 5 mL ofice-cold buffer. The amount of radioactivity on the filters aredetermined by conventional liquid scintillation counting. Specificbinding is total binding minus non specific binding.

Test substances are dissolved in 10 mL water (if necessary heated on asteam-bath for less than 5 min.) at a concentration of 2.2 mg/mL. 25-75%inhibition of specific binding must be obtained before calculation ofIC₅₀. The test value will be given as IC₅₀ (the concentration (nM) ofthe test substance which inhibits the specific binding of ³H-oxo by50%).

IC₅₀=(applied test substance concentration)×(C_(x)/C_(o)−C_(x))nM whereC_(o) is specific binding in control assays and C_(x) is the specificbinding in the test assay. (The calculations assume normal mass-actionkinetics).

Furthermore the pharmacological properties of the compounds of theinvention can also be illustrated by determining their capability toinhibit ³HPRZ (pirenzepine, [N-methyl-³H]) binding to rat cerebralcortex membranes.

Pirenzepine binds selectively t-i subtype of muscarinic receptors.Historically the type is named the M₁-site, whereas pirenzepinesensitive site would be more appropriate. Although selective forM₁-sites porenzepine also interact with M₂-sites.

All preparations are performed at 0-4° C. unless otherwise indicated.Fresh cortex (0.1-19) from male Wistar rats (150-200 g) is homogenizedfor 5-10 s in 10 mL Hepes pH: 7.4, with an Ultra-Turrax homogenizer. Thehomogenizer is rinsed with 2×10 ml of buffer and the combined suspensioncentrifuged for 15 min. at 40,000×g. The pellet is washed three timeswith buffer. In each seen the pellet is homogenized as before in 3×10 mLof buffer and centrifuged for 10 min. at 40,000×g.

The final pellet is homogenized in 20 mM Hepes pH: 7.4 (100 mL per g oforiginal tissue) and used for binding assay. Aliquots of 0.5 mL is added20 μL of test solution and 25 μL of ³HPRZ (1.0 nM, final conc.), mixedand incubated for 60 min. at 20° C. Non-specific binding is determinedin triplicate using atropine (1.0 μg/mL, final conc.) as the testsubstance. After incubation samples are added 5 mL of ice-cold bufferand poured directly onto Whatman GF/C glass fiber filters under suctionand immediately washed 2 times with 5 mL of ice-cold buffer. The amountof radioactivity on the filters are determined by conventional liquidscintillation counting. Specific binding is total binding minusnon-specific binding.

Test substances are dissolved in 10 mL water, at a concentration of 0.22mg/mL. 25-75% inhibition of specific binding must be obtained beforecalculation of IC₅₀.

The test value will be given as IC₅₀ (the concentration (nM) of the testsubstance which inhibits the specific binding of ³HPRZ by 50%).IC₅₀=(applied test substance concentration)×(C_(x)/C_(o)−C_(x))nM whereC_(o) is specific binding in control assays and C_(x) is the specificbinding in the test assay. (The calculations assume normal mass-actionkinetics).

Compounds of this invention showed particularly desirable activity usingthe muscarinic receptor assays. Most compounds were effective at an IC₅₀concentration of less than 10 μMolar (no atropine). The muscariniceffect was confirmed by determining if the effect was blocked byatropine.

II. M4 muscarinic receptor binding assay:

Cyclic AMP Accumulation in Pertussis Toxin-Treated CHO m4 Cells.

CHO K1 cells transfected with human m4 receptors were grown to nearconfluency in T-150 flasks using Dulbecco's Modified Eagle Medium (DMEM)containing 10% fetal bovine serum. Cells were detached with 0.05%trypsin, 0.53 mM EDTA, and were suspended in medium containing 100 ng/mlpertussis toxin. Cells were plated at 30,000 cells per well into 96 wellplates. Eighteen to twenty hours later the medium was removed and thecells were washed with serum-free medium. Attached cells were incubatedat 37_C for one hour after addition of 100 ml of serum free DMEMcontaining 1 mM 3-isobutyl-1-methylxanthine and 1 mM forskolin plus orminus drugs being tested. Incubations were terminated with 200 ml perwell of serum free DMEM containing 0.3%, triton-X-100. After stoppingincubations the plates were allowed to sit for 20 minutes to extractcAMP and samples were then diluted 2.5-fold and were assayed using thescintillation proximity assay of Amersham (Arlington Heights, Ill.).

Representative results from the M4 assay are as follows:

Stimulation of cyclic AMP Production in CHO-m₄ cells.

% Maximum Stimulation Compound Number Compared to Oxotremorine-M 11 3412 26 13 <20 14 100 15 76 17 56 18 61 19 <20 20 69 21 23 22 <20 23 <2024 22 25 43 26 <20 27 <20 28 <20 29 <20 30 <20 31 45 32 <20 33 45 34 4535 65 36 <20 37 76 38 <20 39 43 40 96 41 <20 44 41 45 <20 46 154 47 <2057 5 58 74 59 22 60 100 61 39 62 27 63 13 64 52 65 30 66 0 67 7 68 0 6914 70 18 71 95 72 4 73 11 74 8 75 6 76 130 77 214 88 52 97 36 98 73

III. Psychosis Studies.

The antipsychotic activity of the presently claimed compounds can bedemonstrated in models using well-established procedures. For examplethe compounds are studied to determine if they antagonizeapomorphine-induced climbing behavioral and hypothermia in mice (Moore,N. A. et al. Psychopharmacology 94 (2), 263-266 (1988), and 96, 539(1988)) which measures the ability of the compound to prevent thedisruption of climbing response produced by 24 hour pre-treatment withN-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), a dopaminereceptor inactivating agent (Meller et al. Central D1 dopaminereceptors, Plenum Press, 1988).and/or inhibite a conditioned avoidanceresponse in rats (ED₅₀ 4-7 mg/kg).

The conflict procedure used is based on the method of Geller andSeifter, Psychopharmacologia 1: 482-492, (1960). Rats are trained on amultiple schedule consisting of three components. Individual componentsare as follows: 1) for 9 minutes, lever pressing was reinforced on avariable interval 30 second schedule (VI 30, reward). This period issignaled by illumination of the houselight alone. 2) During thefollowing 3-minute period, lever presses are recorded but had noprogrammed consequence (time-out). 3) Lever pressing is reinforcedaccording to a fixed ratio 10 second food presentation (FR10) for 3minutes; however, each reinforced response is accompanied by an electriccurrent (0.5 mA) being applied to the grid floor for 500 msec(conflicts). This is component is signaled by illumination of thehouselight and three cue lights on the front panel. This sequence ofthree components (reward/time-out/conflict) are presented twice in thesame order during the daily 30 minute session. Animals are givenextensive training on this schedule until the following criteria hadbeen satisfied: 1) rates of responding during the individual VI30components do not differ by more than 10%; 2) rates of responding duringtime-out and conflict are less than 10% of the rate during the VIcomponent; and 3) the above criteria are satisfied for a period of fivedays.

After the training procedure, drug testing is initiated. During thisperiod, the animals are dosed orally with either test compounds orvehicle in a randomized order 60 minutes before testing. At least twodrug-free training days occur between test sessions. This test indicatesthat the compound has anxiolytic properties which are not observed withtypical antipsychotic agents. Spealman et al., J. Pharmacol. Exp. Ther.,212:435-440, 1980.

Further, the pharmacological profile of the claimed compounds isdesirable for use in the treatment of other conditions which are relatedto the mediation of a muscarinic receptor. Such conditions include forexample, Alzheimer's Disease, glaucoma, irritable bowel syndrome,bladder dysfunction and incontinence, treatment of pain, analgesia,Huntington's Disease, epilepsy, Parkinson's Disease, anxiety, and otherpsychotic conditions as described in the DSM-IV.

While it is possible to administer a compound of the invention directlywithout any formulation, the compounds are preferably employed in theform of a pharmaceutical formulation comprising a pharmaceuticallyacceptable excipient and at least one compound of the invention. Suchcompositions contain from about 0.1 percent by weight to about 90.0percent by weight of a present compound. As such, the present inventionalso provides pharmaceutical formulations comprising a compound of theinvention and a pharmaceutically acceptable excipient therefor.

In making the compositions of the present invention, the activeingredient is usually mixed with an excipient which can be a carrier, ora diluent or be diluted by a carrier, or enclosed within a carrier whichcan be in the form of a capsule, sachet, paper or other container. Whenthe carrier serves as a diluent, it can be a solid, semi-solid, orliquid material which, acts as a vehicle, excipient, or medium for theactive ingredient. Thus, the composition can be in the form of tablets,pills, powders, lozenges, sachets, cachets, elixirs, emulsions,solutions, syrups, suspensions, aerosols (as a solid or in a liquidmedium), and soft and hard gelatin capsules.

The compounds of the invention may be delivered transdermally, ifdesired. Transdermal permeation enhancers and delivery systems,including patches and the like, are well known to the skilled artisan.

Examples of suitable carriers, excipients, and diluents include lactose,dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calciumphosphate, alginates, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, tragacanth, gelatin, syrup, methylcellulose, methyl- and propylhydroxy-benzoates, talc, magnesiumstearate, water, and mineral oil. The formulations may also includewetting agents, emulsifying and suspending agents, preserving agents,sweetening agents or flavoring agents. The formulations of the inventionmay be formulated so as to provide quick, sustained, or delayed releaseof the active ingredient after administration to the patient byemploying procedures well known in the art.

The compounds of this invention may be delivered transdermally usingknown transdermal delivery systems and excipients. Most preferrably, acompound of this invention is admixed with permeation enhancersincluding, but not limited to, propylene glycol, polyethylene glycolmonolaurate, and azacycloalkan-2-ones, and incorporated into a patch orsimilar delivery system. Additional excipients including gelling agents,emulsifiers, and buffers may be added to the transdermal formulation asdesired.

For oral administration, a compound of this invention ideally can beadmixed with carriers and diluents and molded into tablets or enclosedin gelatin capsules.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 0.1 to about 500 mg or more, usually about5 to about 300 mg, of the active ingredient. The term “unit dosage form”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect in association with a suitable pharmaceuticalcarrier.

In order to more fully illustrate the operation of this invention, thefollowing formulation examples are provided. The examples areillustrative only, and are not intended to limit the scope of theinvention. The formulations may employ as active compounds any of thecompounds of the present invention.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

Concentration Amount Per by Weight Capsule (percent) A compound of this250 mg 55.0 invention starch dried 200 mg 43.0 magnesium stearate 10 mg2.0 460 mg 100.0

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities.

Formulation 2

Capsules each containing 20 mg of medicament are made as follows:

Concentration Amount Per by Weight Capsule (percent) A compound of this20 mg 10.0 invention starch 89 mg 44.5 microcrystalline 89 mg 44.5cellulose magnesium stearate 2 mg 1.0 200 mg 100.0 mg

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve and filled into a hardgelatin capsule.

Formulation 3

Capsules each containing 100 mg of medicament are made as follows:

Concentration Amount Per by Weight Capsule (percent) A compound of this100 mg 30.00 invention polyoxyethylene 50 mg 0.02 sorbitan monooleatestarch powder 250 mg 69.98 350.05 mg 100.00

The above ingredients are thoroughly mixed and placed in an emptygelatin capsule.

Formulation 4

Tablets containing 10 mg of active ingredient are made as follows:

Concentration Amount Per by Weight Capsule (percent) A compound of this10 mg 10.00 invention starch 45 mg 45.0 microcrystalline 35 mg 35.0cellulose polyvinylpyrrolidone 4 mg 4.0 (as 10% solution in water)sodium carboxymethyl 4.5 mg 4.5 starch magnesium stearate 0.5 mg 0.5talc 1 mg 1.0 100 mg 100.0

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granule so produced isdried at 50°-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate and talc, previouslypassed through a No. 60 mesh U.S. sieve, are then added to the granulewhich, after mixing, is compressed on a tablet machine to yield a tabletweighing 100 mg.

Formulation 5

A tablet formulation may be prepared using the ingredients below:

Concentration Amount Per by Weight Capsule (percent) A compound of this250 mg 38.0 invention microcrystalline 400 mg 60.0 cellulose silicondioxide fumed 10 mg 1.5 stearic acid 5 mg 0.5 665 mg 100.0

The components are blended and compressed to form tablets each weighing665 mg.

Formulation 6

Suspensions each containing 5 mg of medicament per 5 ml dose are asfollows:

per 5 ml of suspension A compound of this invention 5 mg sodiumcarboxymethyl cellulose 50 mg syrup 1.25 ml benzoic acid solution 0.10ml flavor q.v. color q.v. water q.s. to 5 ml

The medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethylcellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor and color is diluted with some of thewater and added to the paste with stirring. Sufficient water is thenadded to produce the required volume.

Formulation 7

An aerosol solution is prepared containing the following components:

Concentration by Weight (percent) A compound of this invention 0.25ethanol 29.75 Propellant 22 (chlorodifluoromethane) 70.00 100.00

The active compound is mixed with ethanol and the mixture added to aportion of the Propellant 22, cooled to −30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted further with the remaining amount of propellant.The valve units are then fitted to the container.

The following Examples further illustrate certain of the compounds ofthe present invention, and methods for their preparation. The examplesare illustrative only, and are not intended to limit the scope of theinvention.

Preparation 1

Indane compounds are formed on a solid polymer support by the a seriesof process steps illustrated by the following 12 steps which arepresented Preparation 1, Example 1 and Example 2, this process isfurther illustrated by Scheme IA, supra.

Steps 1-4 of Synthesis of Scheme IA.

1. To a solution of 1-indanone (25 g, 0.189 mol) in concentrated H₂SO₄(84 ml) at 0° C. was added a solution of KNO₃ (8.33 g, 0.0824 mol) inH₂SO₄ (40 ml) as to maintain an internal temperature below 15° C. Afterstirring at 0° C. for 1 hr., the reaction mixture was poured intocrushed ice and stirred vigorously for 30 min. The suspension was thenfiltered, air dried, and purified by LC (5% ethyl acetate/toluene) toprovide 1^(a) (18.90 g, 56%) as a pale yellow solid.

2. A solution of 1^(a) (18.90 g, 0.107 mol) in methanol (300 ml) wascooled to 0° C. and NaBH₄ (4.04 g. 0.107 mol) was added in several smallportions. The reaction was then stirred overnight at 25° C. The solutionwas quenched at 0° C. with methanolic HCl (200 ml), concentrated underreduced pressure, redissolved in CH₂Cl₂, washed with H₂O, and theorganic layer reconcentrated to provide the crude alcohol as a brownsolid.

3. To a solution of crude alcohol in toluene (300 ml) was added acatalytic amount of p-toluenesulfonic acid and the reaction was refluxedfor 1 hr. using a Dean Stark trap to remove the H₂O. The organic layerwas washed with sat'd. NaHCO₃ (3×200 ml), dried over MgSO₄, solventremoved under vacuum, and the product recrystallized from methanol toafford 3^(a) (13.41 g, 78% over two steps) as a tan solid.

4. To a solution of 3^(a) (10.53 g, 0.0653 mol) in dichloromethane (350ml) at 0° C. was added mCPBA (29 g, 0.0924 mol) in small amounts overthe course of 1 hr. After stirring overnight at 25° C., the mixture waswashed with sat'd Na₂SO₃ (2×200 ml), sat'd NaHCO₃ (2×200 ml), filteredthrough a cotton plug, and concentrated under vacuum. The product shallbe referred to as 4^(a).

EXAMPLE 1

Step 5 of Synthesis of Scheme IA.

5. A suspension of 4^(a) in concentrated NH₄OH (250 ml) was heatedovernight in an oil bath at 45° C. The next day H₂O was added and thebasic aqueous layer was sat'd. with NaCl. The cloudy reaction mixturewas extracted with THF until no more product could be seen by TLC.Organic layers were combined, dried over MgSO₄, concentrated, andrecrystallized from ethyl acetate to give 5^(a) (11.54 g, 91% over twosteps) as a fluffy tan solid. m.p. 148-150° C.

EXAMPLE 2

Step 6 of Synthesis of Scheme IA.

To a solution of 5^(a) (8.34 g, 0.0429 mol) in THF (200 ml) was added asolution of di-tert-butyldicarbonate (11.25 g, 0.0515 mol) in THF (50ml). After stirring 1 hr at 25° C., the solvent was removed underreduced pressure and the resulting solid was recrystallized from ethylacetate to afford 6^(a) (11.37 g, 90%) as a white solid.

Step 7 of synthesis of Scheme IA. Under an N₂ atmosphere a 3 Lthree-necked round bottomed flask equipped with an overhead stirrer andaddition funnel was charged with carboxylated polystyrene resin (70 g,2.77 mmol CO₂H/g resin), anhydrous dichloromethane (1000 ml), andanhydrous DMF (10 ml). Next, oxalyl chloride (50.75 ml, 0.582 mol) wasadded via a slow dropwise addition from an addition funnel. Afterreluxing overnight under N₂, the solvent was removed under vacuum usinga gas dispersion tube. The resin was subsequently washed with anhydrousdichloromethane (3×500 ml). Once the last wash was complete, the resinwas dried under vacuum for 2-3 hrs. At this time, the polymer wasresuspended in dry THF (1000 ml) follwed by the addition of dry pyridine(314 ml, 3.88 mol), DMAP (11.85 g, 0.0970 mol), and 6 (85.62 g, 0.291mol). The mixture was refluxed for 10 days under an inert atmosphere.The solvent was removed by vacuum filtration and the resin was washedwith THF (3×300 ml), CH₂Cl₂ (3×300 ml), and dried overnight in a vacuumoven to provide 7^(a) (122.18 g) as a tan resin.

EXAMPLE 3

Step 8-12 of total synthesis Scheme IA.

Into a round bottomed flask equipped with a stir bar was placed 7^(a)(28 mg, 0.02827 mmol), 0.500 ml dichloromethane, and TFA (0.109 ml,0.14135 mmol). The reaction mixture was stirred at 25° C. overnight,resin collected by filtration, resuspended in 10% TEA/CH₂Cl₂, stirredfor 15 min., filtered again, and finally washed with dichloromethane toafford 8^(a).

9. Into a 10 ml round bottomed flask was placed 7^(a) (0.02827 mmol)followed by 0.5 ml of a solution of pyridine (0.03659 ml, 0.4524 mmol)and DMAP (0.518 mg, 0.004241 mmol) in dichloromethane. Next, a 1Msolution of an electrophile in dichloromethane (0.1838 ml, 0.1838 mmol)was added and the resulting mixture was stirred overnight at 25° C. Atthis time the solvent was removed by vacuum filtration and the resin waswashed with CH₂Cl₂, DMF, methanol, DMF, methanol, and CH₂Cl₂. Thisproduct is referred to as 9^(a).

10. To a solution of 9^(a) (0.02827 mmol) in DMF (0.625 ml) was addedSnCl₂×2 H₂O (102 mg, 0.4524 mmol). Upon stirring at 25° C. for 48 hrs,the resin was isolated by filtration and washed with CH₂Cl₂, DMF,methanol, DMF, methanol, and CH₂ Cl₂ to give 10^(a).

11. Into a 10 ml round bottomed flask was placed 10^(a) (0.02827 mmol)followed by 0.5 ml of a solution of pyridine (0.03659 ml, 0.4524 mmol)and DMAP (0.518 mg, 0.004241 mmol) in dichloromethane. Next, a 1Msolution of an electrophile in dichloromethane (0.1838 ml, 0.1838 mmol)was added and the resulting mixture was stirred overnight at 25° C. Atthis time the solvent was removed by vacuum filtration and the resin waswashed with CH₂Cl₂, DMF, methanol, DMF, methanol, and CH₂Cl₂ to give11^(a).

12. To a flask containing 11^(a) (0.02827 mmol) was added a 1M solutionof NaOH in methanol (0.375 ml, 0.375 mmol) and THF (0.400 ml). Afterovernight stirring at 25° C., the reaction was neutralized with 4M HClin methanol (0.100 ml, 0.400 mmol), resin filtered, and the filtate wasconcentrated under reduced pressure to provide 12^(a).

EXAMPLE 4

A 3 gallon stainless steel hydrogenation reactor was charged with 2.79 g(5% wt. load) of 59. Pd/C under a nitrogen purge. The catalyst was thenwetted with toluene 25 mL). To this mixture was added a solution of 1(55.39 g (0.188 mol) in 3A-EtOH (6 L). After purging the reactor withnitrogen, the reaction vessel was pressurized to 45 psi with hydrogenand stirred at room temperature for 4.5 h. TLC (Silica, 90/10CH₂Cl₂/MeOH+1% NH₄OH) indicated the reaction was complete. The mixturewas filtered through Hi-Flo and the filter cake rinsed with CH₂Cl₂ (2L). The filtrate was transferred to a 12 L Buchii flask and concentratedin vacuo to afford 2 (47.79 g, 96%) as a white solid.

To a solution of 2 (5.0 g, 0.089 mol) in MeOH (50 mL) was addeddimethylformamide-dimethylacetal (3.77 mL, 0.028 mol). After stirring atreflux for 1 h, a second aliquot of dimethylformamide-dimethyl acetal(3.77 mL, 0.028 mol) was added and reflux continued for another 1.5 h.TLC (Silica, 90/10 ethyl acetate/hexanes+2% Et₃N) indicated the reactionwas complete. The mixture was cooled to room temperature andconcentrated to a thick oil. The crude product was dissolved in CH₂Cl₂(100 mL), washed with 1×25 mL D.I. H₂O, 2×50 mL 5% NaHCO₃, and driedover Na₂SO₄. Concentration in vacuo afforded 3 (6.17 g, 96%) as a lighttan foam.

A solution of 3 (1.66 g, 0.0049 mol) in neat pyrrolidine (15 mL) wastreated with 5 mg of (NH₄)₂SO₄ and heated to 80_C in an oil bath. After4 hrs at 80_C, a small aliquot of the reaction mixture was removed,stripped to dryness and analyzed by NMR (CDCl ₃, 500 MHz). Observationof a new amidine-H signal at 7.78 ppm with no signal remaining at 7.52ppm indicated the reasction was complete. The mixture was concentratedto remove the excess pyrrolidine. The resulting crude oil was dissolvedin CH₂Cl₁ (50 mL), washed with 1×25 mL H₂O, 1×25 mL 5% NaHCO₃, and 1×25mL brine, then dried over Na₂SO₄. Concentration in vacuo afforded 4 as atan foam (1.70 g, 95%).

EXAMPLE 5

Compound 4 (1.49 g, 0.0041 mol) was dissolved in cold (−5_C)trifluoroacetic acid (15 mL) and stirred at −5_C to − 10_C for 15minutes. TLC (Silica, 90/10 CH₂Cl₂/MeOH+1% NH₄OH) indicated the reactionwas complete. The mixture was concentrated in vacuo to remove excesstrifluoroacetic acid. The crude oil was dissolved in 2B-EtOH (4 mL) andtreated with the dropwise addition of diethyl ether (30 mL). Theresulting precipitate was filtered, washed with diethyl ether (15 mL)and dried under vacuum at 40_C. Compound 5 (1.70 g, 87%) was recoveredas a white solid.

EXAMPLES 6-105

Examples 6 through 105 were prepared using substantially the proceduredescribed as follows, using the corresponding reagents to provide thedesired compound:

Compound 5 (106 mg, 0.000224 mol) was suspended in CH₂Cl₂ (3.3 mL),cooled to 0_C and treated with Et ₃N (0.09 mL, 0.000894 mol). Theresulting solution was treated with benzoyl chloride (31 mL, 0.000268mol) and the mixture stirred for 0.5 h. With TLC (Silica, 90/10CH₂Cl₂/MeOH+1%. NH₄OH) showing the reaction to be complete, the mixturewas diluted with CH₂Cl₂(2.5 mL) and quenched with H₂O (2.5 mL). Theorganic layer was washed with 1×5 mL H₂O, 3×2.5 mL 5% NaHCO₃, and 1×2.5mL brine. After drying over Na₂SO₄, the mixture was concentrated invacuo to afford 6 (76 mg, 97%) as a white foam.

EXAMPLES 6-105

Examples 6-105 are presented in the following table. The “Comp.#”corresponds to both the compound number and example number.

R** is

wherein R², R¹¹, R¹², and R¹³ are defined as described supra.

Electros pray Ionizati Comp. on M.S. # R** R¹¹ R² (M + 1) 6 1- H Phenyl350 Pyrrolidine 7 1- H 3,5 486 Pyrrolidine di(trifluoro- methyl)-phenyl8 1- H 4-Butoxy-Phenyl 422 Pyrrolidine 9 1- H Cyclopentyl 342Pyrrolidine 10 1- H 6-Chloro-3- 385 Pyrrolidine Pyridinyl 11 1- HCyclohexyl 356 Pyrrolidine 12 1- H 2-Chloro-3- 385 Pyrrolidine Pyridinyl13 1- H 4-Cyano-Phenyl 375 Pyrrolidine 14 1- H 3,5 419 Pyrrolidinedichlorophenyl 15 1- H 1-Napthyl 400 Pyrrolidine 16 1- H 4-Ethylphenyl378 Pyrrolidine 17 1- H 2-Napthyl 400 Pyrrolidine 18 1- H 4- 418Pyrrolidine Trifluoromethyl- Phenyl 19 1- H Trifluoromethyl 342Pyrrolidine 20 1- H 2-Chloro-4- 429 Pyrrolidine Nitro-Phenyl 21 1- H2-Thiophene 356 Pyrrolidine 22 1- H 4-Tosyl 396 Pyrrolidine 23 1- H 3,5difluoro 386 Pyrrolidine Phenyl 24 1- H 2,3 difluoro- 386 pyrrolidinePhenyl 25 1- H 3-Nitro-Phenyl 395 Pyrrolidine 26 1- H 4-Propylphenyl 392Pyrrolidine 27 1- H 2,4,6 392 Pyrrolidine Trimethylphenyl 28 1- HMethylenethio- 396 Pyrrolidine phenyl 29 1- H 2,3,6 404 PyrrolidineTrifluorophenyl 30 1- H 3-Fluorophenyl 368 Pyrrolidine 31 1- H 2,3 419Pyrrolidine Dichlrophenyl 32 1- H 2,5 386 Pyrrolidine Difluorophenyl 331- H 2,3,4 404 Pyrrolidine Trifluorophenyl 34 1-Pyrroldine H3-Methoxy-Phenyl 380 35 1- H 2- 418 Pyrrolidine Trifluoromethyl Phenyl36 1- H 3,5 Dimethoxy- 410 Pyrrolidine Phenyl 37 1- H 3-Tolyl 364Pyrrolidine 38 1- H 3-Cyano-Phenyl 375 Pyrrolidine 39 1- H 3,4,5Trifluoro- 404 Pyrrolidine Phenyl 40 1- H 2,3,4,5 422 PyrrolidineTetrafluoro- Phenyl 41 1- H Cyclobutyl 328 Pyrrolidine 42 1- H2-Methoxy-Phenyl 380 Pyrrolidine 43 1- H 2-Tolyl 364 Pyrrolidine 44 1- H2-Chlorophenyl 384 Pyrrolidine 45 1- H 4-Butyl-Phenyl 406 Pyrrolidine 461- H 2,6 419 Pyrrolidine Dichlorophenyl 47 1- H 2,4,6 Trichloro- 453Pyrrolidine Phenyl 48 1- H 2-Quinoxyl 402 Pyrrolidine 49 1- H 2,4,5Trifluoro- 404 Pyrrolidine Phenyl 50 1- H 2,6 Difluoro- 386 PyrrolidinePhenyl 51 1- H 2-Iodophenyl 476 Pyrrolidine 52 1- H 2,4 386 PyrrolidineDifluorophenyl 53 1- H Undecanyl 414 Pyrrolidine 54 1- H 4-Ethoxy-Phenyl394 Pyrrolidine 55 1- H 4- 436 Pyrrolidine Trifluormethyl-5-Fluoro-Phenyl 56 1- H 2- 436 Pyrrolidine Trifluoromethyl-6-Fluoro-Phenyl 57 Dimethyl- H Phenyl 324 amine 58 Dimethyl- H 3,5 393amine Dichlorophenyl 59 Dimethyl- H 4-Butoxy-Phenyl 396 amine 60Dimethyl- H 3,5 di- 460 amine (trifluoro- methyl)-Phenyl 61 Dimethyl- H3-Cyano-Phenyl 349 amine 62 Dimethyl- H Cyclopentyl 316 amine 63Dimethyl- H 2-Napthyl 374 amine 64 Dimethyl- H 3- 410 amineTrifluoromethyl- 5-Fluoro-Phenyl 65 Dimethyl- H 3,4,5 Trifluoro- 378amine Phenyl 66 Dimethyl- H Trifluoromethyl 316 amine 67 Dimethyl- H4-Ethyl-Phenyl 352 amine 68 Dimethyl- H 3-Chloro-2- 364 amine Thiophene69 Dimethyl- H 2-Benzothiophene 380 amine 70 Dimethyl- H 4-Butyl-Phenyl380 amine 71 Dimethyl- H 1-Napthyl 374 amine 72 Dimethyl- H 3,4Dichloro- 429 amine Benzenesulfonyl 73 Dimethyl- H 2-Chloro-3- 359 aminePyridinyl 74 Dimethyl- H 6-Chloro-3- 359 amine Pyridinyl 75 Dimethyl- H4- 392 amine Trifluoromethyl- Phenyl 76 Dimethyl- CH₃ 3,4 407 amineDichlorophenyl 77 1-Piperidine H 3,4 433 Dichlorophenyl 78 1-PiperidineH 3- 448 Trifluoromethoxy- Phenyl 79 1-Piperidine H 3-Fluorophenyl 38280 1-Piperidine H 3-Chlorophenyl 398 81 1-Piperidine H 3-Methoxy-Phenyl394 82 1-Piperidine H 3- 432 Trifluoromethyl- Phenyl 83 1-Piperidine H2-Tolyl 378 84 1-Piperidine H 2,4 433 Dichlorophenyl 85 1-Piperidine H2-Chloro-4- 444 Nitro-Phenyl 86 1-Piperidine H 4-Propyl-Phenyl 406 871-Piperidine H 4-Methoxyphenyl 394 88 1-Piperidine H 2,3 433Dichlorophenyl 89 1-Piperidine H 3,4,5 418 Trifluorophenyl 901-Piperidine H 3,5 Dimethoxy- 424 Phenyl 91 1-Piperidine H 3-Nitrophenyl409 92 1-Piperidine H 3,4 400 Difluorophenyl 93 1-Piperidine H 3,5 di-500 (trifluoromethyl)- Phenyl 94 1-Piperidine H 3,4 424 Dimethoxyphenyl95 1-Piperidine H 4-Cyano-Phenyl 389 96 1-Piperidine H 4-Ethylphenyl 39297 1-Piperidine H 3,5 433 Dichlorophenyl 98 1-Piperidine H 3,5 400Difluorophenyl 99 1-Piperidine H 3-Bromophenyl 443 100 1-Piperidine H4-Butylphenyl 420 101 1-Piperidine H 3-Cyanophenyl 389 102 1-PiperidineH 2-Iodophenyl 490 103 1-Piperidine H Phenyl 364 104 1-Piperidine H4-Nitrophenyl 409 105 1-Piperidine H Trifluomethyl 356

EXAMPLE 106 6-amino-1-indanone t-butylcarbamate, 106

A mixture of 6-amino-1-indanone (4.41 g) and EtOAc (250 mL) was treatedwith di-t-butyl-di-carbonate (7.2 g) and the reaction stirred two days.After addition of K₂CO₃ (4 g), the reaction was heated to 70 C overnight. The mixture was cooled and treated with cold H₂O and extractedwith EtOAc. The organics were washed with saturated aqueous citric acidand brine then the solvent was dried and evaporated to give a darkviscous oil that solidified. The material was further purified by hplceluting with 20% EtOAc-hexane to give a floculant tan solid (5.1 g).

EXAMPLE 107 2-amino-6-t-butylcarbamido-indane,107

A mixture of 106 (2.5 g), THF (75 mL), ammonia (25 mL), and Pt/C—S (0.9g) was treated with H₂ at 1000 psi for 8 h at 140 C. The catalyst wasremoved by filtration and the solvent evaporated to give a foam that waspurified by radial chromatography eluting with 20% EtOH-2%-NH₄OH-CHCl₃,to give a white solid (0.9 g).

EXAMPLE 108 2-m-trifluoromethylbenzamido-6-t-butylcarbamido-indane, 108

A solution of 107 (0.9 g) and a catalytic amount of4-dimethylaminopyridine in pyridine (10 mL) was cooled in ice-water asm-trifluoromethylbenzoyl chloride (0.9 g) was added dropwise. Thecooling was removed and the reaction was stirred over night. The solventwas evaporated, the residue treated with cold H₂O, and the mixtureextracted with EtOAc. The extracts were washed with H₂O, 0.2 N HCl, H₂O,aqueous NaHCO₃, the solvent dried and then evaporated to give a whitesolid (1.42 g).

EXAMPLE 109 6-amino-2-m-trifluromethylbenzamido-indane, 109

A solution of 108 (1.4 g) in EtOAc was cooled in ice-water and treatedwith a stream of dry HCl for 2 min. After another 10 min, the solventwas evaporated, the residue suspended in cold water, and the mixturemade basic. The mixture was extracted with ether, the ether washed withbrine, the solvent then dried and evaporated to give a white solid (1g).

EXAMPLE 110 6-dimethylformamidino-2-m-trifluoromethylbenamido-indane,110

A mixture of chloromethylene-dimethylammonium chloride (0.1 g) andCH₂Cl₂ (5 mL) was treated with 109 (0.16 g). The reaction was thentreated with triethylamine (0.3 mL) and after 5 min, the solvent wasevaporated. The residue was treated with ice-water, the mixture wasacidified, and the mixture extracted with ether. The aqueous phase wasmade basic, the mixture was extracted with ether, and the extractswashed with water and brine. The solvent was evaporated and the residuepurified by radial chromatography eluting with 10% EtOH-CHCl. The HClsalt crystallized from EtOAc-acetone as a white solid (70 mg), m.p. 239C, dec.

EXAMPLE 111 6-nitro-1,2-dihydronapthalene, 111

A suspension of 7-nitrotetralone (20 g, 0.105 mol) in MeOH (300 mL) wastreated with NaBH₄ (4.1 g) with intermitent cooling. After the addition,cooling was removed and the reaction stirred over night. The reactionwas cooled in ice-water and quenched with a solution of MeOH (200 mL)and concentrated HCl (35 mL). The solvent was evaporated, the residuewas suspended in H₂O, and the mixture was extracted with CHCl. Theextracts were dried and the solvent evaporated to give a tan solid. Amixture of the solid, p-toluenesulfonic acid (0.4 g), and toluene (300mL) was heated to reflux for over night with water being collected in aDean-Stark trap. The reaction was cooled, washed with H₂O, aqueousNaHCO₃, and brine, then the solvent was dried and evaporated to give adark liquid (15.6 g) that had an nmr consistent with the desiredmaterial.

EXAMPLE 112 (±)-trans-1-amino-2-hydroxy-7-nitrotetraline,112

A solution of 111 (15.6 g) in CH₂Cl₂ (400 mL) was cooled in ice-waterand m-chloro-peroxybenzoic acid (42 g of 50-55% pure material) was addedin portions over 1 h. Excess oxidant was then destroyed with aqueoussodium thiosulfate. The reaction was filtered and the organics washedwith aqueous NaHCO₃ and brine, then the solvent was dried and evaporatedto give a yellow solid (16.9 g). The solide was suspended in ammoniumhydroxide (550 mL) and the mixture heated to 55° C. for 72 h. The solidwas collected by filtration and recrystallized from MeOH to give afloculant white solid, m.p. 216-218 OC (12.3 g).

EXAMPLE 113(±)-trans-1-(3,4-dichlorobenzamido)-2-hydroxy-7-nitrotetraline,113

A solution of 112 (2.1 g) in warm THF (300 mL) was treated withtriethylamine (5 mL) and the solution allowed to come to roomtemperature. A solution of 3,4-dichlorobenzoyl chloride (2.3 g) in THF(50 mL) was added dropwise over 20 min. After stirring over night, thesolvent was evaporated to give a solid (3.97 g) that had the appropriatenmr spectrum.

EXAMPLE 114(±)-trans-1-(3,4-dichlorobenzamido)-2-acetoxy-7-nitrotetraline, 114

A mixture of 113 (1.9 g, 0.005 mol) in THF (200 mL), triethylamine (1.3mL), and a catalystic amount of 4-dimethylaminopyridine was treated withacetic anhydride (0.9 mL). After stirring over night, the solvent wasevaporated and the residue treated with H₂O. After 2 h, the mixture wasextracted with EtOAc. The extracts were washed with 1 N H₂SO₄, brine,aqueous NaHCO₃, and brine, then the solvent was dried and evaporated togive a floculant white solid (1.94 g) that had the appropriate nmr forthe desired material.

EXAMPLE 115(±)-trans-1-(3,4-dichlorobenzamido)-2-acetoxy-7-aminotetraline, 115

A solution of 114 (1.9 g) in DMF (100 mL) was treated with SnCl₂H₂O (4g). After 4 h, additional SnCl₂—2H₂O (1 g) was added three times overthree days. The solvent was then evaporated, the residue suspended inH₂O-EtOAc, the mixture neutralized with 5N NaOH, and the mixturefiltered. The organics were separated, washed with brine, dried, and thesolvent evaporated to give a brown foam (1.9 g).

EXAMPLE 116(±)-trans-1-(3,4-dichlorobenzamido)-2-acetoxy-7-(pyrrolidinoformamido)tetraline,116

A solution of pyrrolidine carboxamide (1.5 mL) in CH₂Cl₂ (25 mL) wastreated with POCl₃ (0.23 mL). After 1.5 h, the solution was treated withtriethylamine (1 mL) and 115 (0.5 g). After stirring over night, thesolvent was evaporated, the residue was treated with ice-water, themixture neutralized, and the mixture extracted with EtOAc. The extractswere washed with brine and the solvent was dried and evaporated to givea dark oil. The oil was purified by radial chromatography eluting with5% EtOH-CHCl₃ to give a tan solid that was recrystallized from EtOAc togive a white solid (0.18 g), m.p. 229° C., dec.

EXAMPLE 117(±)-trans-1-(3,4-dichlorobenzamido)-2-hydroxy-7-(pyrrolidinoformamido)tetraline,117

A solution of 116 (0.27 g) in MeOH (10 mL) was treated with 0.135 Msodium methoxide (4.9 mL) in MeOH. After 4 h, the solvent wasevaporated, the residue was suspended in H₂O, and the solid wascollected by filtration. The solid was crystallized from EtOAc-ether togive a tan powder, m.p. 206-208° C.

What is claimed is:
 1. A compound of the Formula III′

R¹ is selected from the group consisting of hydrogen, —OR⁴, —SR⁵, C₁-C₃alkyl, C₂-C₃ alkenyl, halo, —CN, —COR^(4b′), and —OC(O)—R¹⁵; m2 is from0 to 2; R⁴ is hydrogen, C₁-C₃ alkyl; R⁵ is hydrogen, C₁-C₃ alkyl; R¹⁰ isselected from the group consisting of hydrogen, carbonyl, halo, andC₁-C₃ alkyl; R¹¹ is selected from the group consisting of hydrogen andC₁-C₃ alkyl; R¹² is independently selected from the group consisting ofhydrogen, C₁-C₁₀ alkyl, and aryl; R¹³ is independently selected from thegroup consisting of hydrogen, C₁-C₁₀ alkyl, and aryl; or R¹² and R¹³together with the nitrogen to which they are attached form a group ofthe formula II:

II′ wherein the II′ group is a group of Formula II which is unsaturated;or R¹¹ and R¹² together with the nitrogen and carbon to which they arebound can join to form a three to six membered ring; R¹⁴ is selectedfrom the group consisting of H, halo, C₁-C₃ alkyl, S(O)_(m3) and —OR¹⁶;R¹⁵ is C₁-C₃ alkyl or aryl; R¹⁶ is C₁-C₃ alkyl; R¹⁷ is independentlyselected from the group consisting of hydrogen, —OR^(4′), —SR^(5′),C₁-C₃ alkyl, C₂-C₃ alkenyl, halo, —CN, S(O)_(m2′), —COR^(4b), and—OC(O)—R¹⁵; R^(4b) and R^(4b′) are each independently selected fromhydrogen and C₁-C₃ alkyl; R^(15′) is C₁-C₃ alkyl or aryl; m2′ is 0 to 2;R^(4′) is hydrogen, C₁-C₃ alkyl; R^(5′) is hydrogen, C₁-C₃ alkyl; m2 is0 to 2; X is selected from the group consisting of C, O, S, N, carbonyl,and a bond; n′ is 0 to 2; m′ is 0 to 2; m3 is 0 to 2; n is 0 to 3; R²⁰is selected from the group consisting of benzyl, 3,4-dimethoxybenzyl,o-nitrobenzyl, and triphenylmethyl; carbamates of the formula —COORwheren R is selected from the group consisting of methyl, ethyl, propyl,isopropyl, 2,2,2-trichloroethyl, 1-methyl-1-phenylethyl, isobutyl,t-butyl, t-amyl, vinyl, allyl, phenyl, benzyl, p-nitrobenzyl,o-nitrobenzyl, and 2,4-dichlorobenzyl; and formyl; or a pharmaceuticallyacceptable salt or solvate thereof.
 2. A compound of claim 1 wherein R²⁰is a carbamate of the formula —COOR wheren R is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, 2,2,2-trichloroethyl,1-methyl-1-phenylethyl, isobutyl, t-butyl, t-amyl, vinyl, allyl, phenyl,benzyl, p-nitrobenzyl, o-nitrobenzyl, and 2,4-dichlorobenzyl.
 3. Acompound of claim 2 wherein R²⁰ is t-butoxycarbonyl.
 4. A compound ofclaim 1 wherein R¹ is OH.
 5. A compound of claim 3 wherein R¹ is OH.